HerbalEGram: Volume 9, Number 1, January 2012

The statutory language and complexity of issues associated with the NDI provision—sometimes referred to as Section 8 of DSHEA—makes it difficult to interpret and understand, even by lawyers and regulatory experts. ABC Founder and Executive Director Mark Blumenthal noted this in ABC’s formal comments submitted to FDA in 2005, following a public meeting on the subject the previous year. “ABC has been concerned that industry, media, health professionals, and other areas of the general public have not adequately understood or appreciated the significance of Section 8 of DSHEA, the New Dietary Ingredient provision,” he wrote.¹

On July 1, 2011, just days before the FSMA deadline, FDA released a draft guidance document designed to clarify the NDI process. However, many of the original concerns of ABC and other parties were not adequately addressed, and industry trade organizations are generally displeased with the document. Marc Ullman, of Ullman, Shapiro & Ullman, LLC, a firm that specializes in food and drug law, called the draft guidance document “unfortunately myopic” and “fatally flawed” in comments submitted to FDA in August 2011.²

In an authoritative letter to FDA Commissioner of Food and Drugs Margaret Hamburg, MD, Sens. Hatch and Harkin suggested the draft guidance would create “substantial, additional costs on manufacturers without providing additional safety benefits, and would undermine the access to safe, affordable dietary supplement products that DSHEA was designed to ensure.”³

Other notable groups that filed comments include the National College of Natural Medicine (NCNM), the American Association of Naturopathic Physicians (AANP), and the 5 dietary supplement trade associations—the American Herbal Products Association (AHPA), the Consumer Healthcare Products Association (CHPA), the Council for Responsible Nutrition (CRN), the Natural Products Association (NPA), and the United Natural Products Alliance (UNPA).

According to AHPA, which submitted 75 pages of comments, the draft guidance will simply not suffice. “[I]f implemented as written … [the draft guidance would] change the rules that have been in place for the last 17 years and significantly increase the burden on the supplement industry,” wrote AHPA President Michael McGuffin.⁴

According to Section 8 of DSHEA, manufacturers and distributors of dietary ingredients not marketed before the passage of DSHEA on October 15, 1994—and not present in the food supply in a form in which the food has not been chemically altered—are required to notify FDA at least 75 days before introducing the ingredient to the market.⁵ The notification must contain adequate information to demonstrate a reasonable expectation of safety of the new dietary ingredient under ordinary or labeled conditions of use for the dietary supplement. (Ingredients sold prior to this date are often unofficially referred to as “grandfathered” or “old dietary ingredients” [ODIs].)

DSHEA created a new safety standard for dietary ingredients used in supplements. Under the law, FDA may deem a product adulterated—and therefore illegal—if it does not meet one of the following 2 requirements:

(1) “The dietary supplement contains only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered.”

(2) “There is a history of use or other evidence of safety establishing that the dietary ingredient when used under the conditions recommended or suggested in the labeling of the dietary supplement will reasonably be expected to be safe; and … the manufacturer or distributor of the dietary ingredient or dietary supplement provides the FDA with information, including any citation to published articles, which is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably expected to be safe.”⁵

If a new dietary ingredient is not present in the food supply as an article used for food in a form in which the food has not been chemically altered, the manufacturer or distributor of the ingredient must submit notification to FDA along with data establishing the NDI’s safety (that is, that the NDI will reasonably be expected to be safe when used under conditions of use recommended in labeling for the dietary supplement or under ordinary conditions of use).  

Claire Kruger, PhD, of Spherix, a health products consulting firm, offered examples of tests that could help satisfy this requirement in a September 2011 presentation hosted by Natural Products Insider (NPI). “[A]nimal studies offer a well-controlled atmosphere,” she suggested. “Other options include a genotoxicity battery; repeat dose toxicity; chronic/carcinogenicity; reproductive, developmental/teratology, and absorption, distribution, metabolism, and elimination (ADME) studies.”⁶

A special report published in November 2011 by NPI looked at the industry’s general understanding of the draft guidance document. Forty-four percent of the 217 respondents identified themselves as supplement manufacturers/marketers, followed by 23% who considered themselves ingredient suppliers.⁷ Out of 7 possible areas of concern, survey respondents (82%) were most concerned with the cost of compliance.

According to Dr. Kruger, who spoke at UNPA’s 2-day NDI seminary in June 2011, study expenses can range from approximately $6,000 for a genetic toxicity battery to more than half a million dollars for a multi-generation rodent reproductive study.⁸ Extensive rodent studies, however, are usually needed only in cases where there is virtually no pre-existing safety data.

Some say the added costs of these studies could lead to adverse consequences for the industry as well as consumers. “This would lead to higher consumer prices, reduced variety of product choices, contraction of jobs and innovation, and would foster an inequitable competitive environment between manufacturers,” wrote UNPA Executive Director Loren Israelsen in his organization’s 2011 comments to FDA.⁹ However, FDA expects that these safety studies should already have been conducted by the company, as the law states that manufacturers must ensure the safety of their product. Therefore, FDA does not take these study costs into consideration.

According to the most recent figures available, FDA has received approximately 700 NDI notifications since the passage of DSHEA in 1994. This figure, which FDA officials have suggested represents a relatively low level of compliance, has been explained by some industry members as a result of general confusion surrounding the NDI provision and also on the potential cost of acceptable safety tests.¹⁰

“FDA has stated its view that there is only a ‘minimum burden’ on companies that need to generate data to meet the requirement to submit a NDI notification,” McGuffin noted. “The agency explains its rationale for this evaluation by ignoring any effort required to develop the information on which a NDI manufacturer or distributor has based its conclusion that a dietary supplement that contains the NDI will reasonably expected to be safe.”⁴

“However, with that stated, this is a guidance, it does not convey any new binding authority to the agency, it only clarifies our thinking on the topic. Should there be increased enforcement/regulatory action on NDIs, it would simply be coincidental,” Dr. Fabricant added.

Old or New?

One of the most basic concerns of industry leaders is the lack of an FDA-approved list of ODIs. Without such a list, determining which ingredients are NDIs is becoming exceedingly difficult. Seventy-five percent of respondents to the NPI survey said they were “very/a lot concerned about requirements to prove an ‘Old Dietary Ingredient.’”⁶

Notwithstanding FDA’s draft guidance, under DSHEA a company is not legally required to prove to FDA that a dietary ingredient is an ODI prior to marketing. Dietary supplement companies (manufacturers, marketers, and distributors) should be prepared, however, to defend the regulatory status of dietary ingredients (and other ingredients) used in their dietary supplements. Companies must exercise due diligence prior to marketing to fully vet the ODI vs. NDI issues. In the event that FDA pursues an enforcement action against a company asserting that a dietary supplement is adulterated because it contains an NDI for which there is inadequate information to provide reasonable assurance that the ingredient does not present a significant or unreasonable risk of illness or injury, the government will bear the burden of proof to show that the dietary supplement is adulterated under DSHEA.

At the time of DSHEA’s enactment, there was a general assumption that dietary ingredients sold before DSHEA’s passage were considered to be safe based on widespread consumer use.  “That’s not to say FDA couldn’t remove one of those ingredients from the marketplace; but, to do so, the burden would be on the agency,” wrote CRN President Steve Mister in a July 2011 NPI article. “And if FDA could demonstrate a product carried ‘an unreasonable or significant risk of injury of illness,’ it could remove that product from the market. FDA did just that with ephedra.”¹¹

Now, it seems, the agency is attempting to shift the burden of proof to the industry. According to Dr. Fabricant, “There needs to be independent, verifiable evidence that the article itself has been offered for sale in the US as a dietary supplement pre-DSHEA. (Examples: catalogs, price lists, business records [e.g., invoices, shipping records, bills-of-lading]; and advertisements).”⁹ However, almost 17 years after the passage of DSHEA, these paper documents are often not readily available or accessible and, with each year, continue to disappear.

Ingredients Versus Supplements

Some members of the dietary supplement industry were also surprised at the guidance document’s insistence on submitting notifications for all supplements containing an NDI, even if the supplement contains an NDI included in a pre-existing FDA notification, and all the other dietary ingredients in the product were marketed prior to October 15, 1994. Seventy-three percent of respondents to the NPI survey were very concerned “about the restrictive definition of ‘dietary ingredient’ and the need to file for each finished product rather than for each ingredient.”⁷

“It seems that a NDI notification must be submitted to FDA for each individual formula that contains the NDI,” wrote Shaheen Majeed and Benoit LeGall in their comments from Sabinsa Corporation, a manufacturer of botanical extracts. “This not only places a tremendous burden on ingredient and finished product manufacturers, but it will constitute an unmanageable burden on the Agency, potentially undermining the Agency’s ability to act on more pressing regulatory issues such as adulteration.”¹²

In comments filed jointly, CRN and CHPA also criticized the assumed practicality of requiring notifications for each individual supplement containing an NDI. “Such a policy is not grounded in practical realities or science,” they wrote. “And it would result in industry members submitting burdensome and duplicative notifications that waste both industry and agency resources without providing any consumer safety benefit.”¹³ (However, a reviewer of this article noted that FDA has already commented that NDI applications that cover the NDI used in a range of doses, intended uses, and with a range of combinations of ingredients are acceptable.)

AHPA—a leader in industry discussions of NDIs—maintains a database of NDI notifications online; however, there is no seal of approval for any ingredient or supplement that “passes” the inspection (i.e., that receives a letter of no objection from FDA). “FDA states that each NDI submission is applicable and specific to the submitter. Other companies intending to market the same ingredient would have to submit their own NDI submission,” wrote Chris and Patrick Noonan in a 2004 HerbalGram article marking the 10^th anniversary of DSHEA’s passage. “In other words, there are no generic submissions that will benefit all other companies using the same ingredient.” ¹⁴

Still, members of the industry are not satisfied with FDA’s interpretation of the statute. Industry representatives maintain that the massive amount of NDI notifications that need to be filed could ultimately result in products being pulled from the market.

“If industry took FDA’s directive and literally began filing NDIs on all these ‘new’ ingredients, it could overwhelm the agency,” wrote Mister. “[It could] result in trusted ingredients with strong safety records being removed from the market until FDA reviews the notice and responds.”¹⁶

Chemical Alteration and Solvents

In addition to industry’s general concerns, questions have also been raised about the statute’s definition and meaning of “chemically altered.” This term is defined in the Statement of Agreement, which, according to the chief sponsors of DSHEA, comprises the entire legislative history for the bill. “Chemically altered” is defined by what is not included, namely, the following physical modifications: minor loss of volatile components, dehydration, lyophlization (freeze-drying), milling, tincture or solution in water, slurry, powder, or solid in suspension.”⁵

If an ingredient is “chemically altered,” even if it was marketed in a more basic form (e.g., a whole herb powder or an herbal tincture) before October 15, 1994, the manufacturer or supplier of the ingredient is required to submit a notification and safety data to FDA. However, almost 2 decades since passage of DSHEA, advances in technology have provided new, safer methods of preparation for botanical and other dietary ingredients that could not have been predicted at the time—technologies and processes that ought not per se trigger FDA premarket notification requirements, according to numerous comments.

To illustrate, supercritical carbon dioxide extraction is often cited as an example of a process that, although known to be safe, would require a NDI notification. “Carbon dioxide (CO2) is a direct food substance affirmed as Generally Recognized as Safe (GRAS),” Sabinsa Corporation noted in its 2011 comments. “Due to the health, environmental and safety concerns associated with the use of some organic solvents and the possible solvent contamination of the final product, supercritical fluid extraction, using CO2, as an extraction fluid, offers an excellent alternative to the use of chemical solvents. Carbon dioxide leaves no reside or causes no damages to the ingredient profile.”¹²

Because DSHEA was enacted as part of an effort to ensure the accessibility and safety of a range of dietary ingredients in dietary supplements, various experts have expressed concern that the language in FDA’s draft NDI guidance document is contrary to the true intent of the law. “ABC believes that the emphasis for the matter of determining whether an NDI notification should be made should focus on the safety (which implicates chemical profile) of the resulting extract, not the process by which it is made nor the solvent(s) that is/are used in the extraction process,” said Blumenthal.¹⁰

However, some argue that these measures are specifically designed to increase product safety. At UNPA’s 2011 conference on FDA’s NDI Draft Guidance, Nancy Booth, a scientific consultant from Spherix, said that virtually any type of processing—even water extraction—could introduce environmental contaminants and therefore should be regulated appropriately.¹⁸ Other industry experts insist that the Good Manufacturing Practices (GMP) regulations, which focus on how products are manufactured and impose requirements to prevent adulteration in processing, are the proper method to address these concerns, and that NDI requirements should focus on the safety of the underlying ingredient, not the manufacturing process.

Regardless of the intent of DSHEA, if FDA were to enforce the NDI provision according to its draft guidance, the number of NDI notifications would undoubtedly increase significantly. FDA, however, insists that clarification of this process will result in a smoother process. “The second goal of the guidance is to enhance the quality of those submissions, so although we will be receiving a higher volume, the increased quality of the information will reduce the amount of follow-up necessary and thus servicing to offset the influx,” said Dr. Fabricant.¹⁰

In the years since the passage of DSHEA, advances in technology have also allowed industry members to effectively create synthetic versions of some ingredients, and other novel ingredients such as bacteria (e.g., probiotics) are increasingly included in supplements.

Today, scientists are able to create compounds in a lab that are indistinguishable from those found in nature. Ingredient suppliers may choose to synthesize certain ingredients for environmental, quality-control, or economic reasons, said Blumenthal.

Mister of CRN urges FDA to consider the bigger picture. “What’s particularly troubling is that this isn’t even a question of safety. To FDA, it’s definitional—if the [botanical] ingredient is produced in a lab, no matter how bio-identical it is—it can’t be used in a dietary supplement, period. And no amount of safety data appears that it will change the agency’s mind,” he said.¹⁸

FDA has not yet specifically expounded on non-botanical [and non-vitamin] synthetic ingredients, e.g., synthetic co-enzyme-Q10 or L-carnitine. On that basis, these synthetic ingredients can be considered legal dietary ingredients. Further, synthetic botanical constituents that are also GRAS or approved food additives can also be legal dietary ingredients.

Further, the focus on digestive health in recent years has led to the marketing of many products with beneficial bacteria, as noted by Sabinsa Corporation in its comments. “In the draft guidance section IV.C.3, FDA simply states that ‘bacteria that have never been consumed as food are unlikely to be dietary ingredients.’ With this statement, FDA appears to eliminate all new probiotic strains, which have not been consumed yet as food, from consideration as dietary ingredients.”¹²

According to Dr. Fabricant, when it comes to the law as written, it is a matter of semantics. “Ingredients need to be dietary ingredients before they can be NDIs,” he said. “Synthetic botanicals and probiotics may not lie in the diet, and thus may better fit into the food additive category. It’s up to product manufacturers to prove probiotics were in the diet of man before they were isolated as an ingredient and used in a dietary supplement or as a GRAS ingredient.”⁶

Despite the impassioned reactions from concerned parties after the publication of the draft guidance, the passage of DSHEA is still seen as a boon to the dietary supplement industry. A July 2011 NDI article described it as “a big win for the industry [that] set up several principles that has allowed industry to thrive to this day, including supplements being regulated as foods rather than drugs…. and supplements not requiring FDA preapproval.”¹⁹

However, the publication of the draft guidance threatens that legacy according to some industry spokespeople. The general consensus from many industry members is that the draft guidance document is a move by FDA to increase regulation of dietary supplements and dietary ingredients, setting up a premarket approval system that was not the intent of Congress in enacting DSHEA. “It would appear… that the Agency is intending to use this guidance as a means to create a non-statutory pre-market approval system vehicle for any dietary ingredient that the Agency deems is an NDI,” Blumenthal wrote.²⁰

Dr. Fabricant maintains that the draft guidance document is consistent with the language of DSHEA. “Guidance documents are not usually enforceable rules or requirements by themselves, but serve more to define standards and expectations and in this case it would be to more clearly communicate the new dietary ingredient requirements under [DSHEA],” he said.¹⁰

In addition to calling for withdrawal and revisions to the document, steps are already being taken to change the law. Representative Dan Burton (R-IN) introduced a new bill in 2011 designed to ease the burden of the NDI provision. The bill, known as the “Dietary Supplement Protection Act,” moves the ODI deadline date of October 15, 1994 to a more recent date in early 2007, effectively grandfathering supplement ingredients marketed before that date. The virtually untarnished safety record of dietary supplements, according to industry supporters, supports this change.²¹

In addition to concerns previously addressed, the nutrition, weight-management, and personal care products company Herbalife recommended that FDA simplify the NDI notification process and increase transparency by using NDI master files that can help FDA protect intellectual property or trade secrets that may be included in an NDI submission. The master file system would also make the notification process easier because submitters could cite the master file as part of the notification rather than needing to generate additional safety data on the same ingredient.²²

In order to increase the efficiency of the NDI notification process, Herbalife proposed that FDA check for all required components before starting the 75-day countdown. FDA could then proceed to a review of safety data and accept or reject the notification, if appropriate. “Once implemented, a procedure like this would offer FDA, industry, and observers (Congress, the public, interest groups) an easy way to know the status of any pending NDI filing and to plan product development,” Herbalife said in its public comments on the draft guidance.²²

To date, FDA has received an estimated 149,000 pages of comments regarding the July 2011 draft guidance documents.⁷ Much time is needed, they say, to review all of the comments before proceeding with an official response. The timeline for action is currently unknown.

“[W]e absolutely don’t want this to just sit around as a draft for years,” said Duffy McKay, ND, vice-president of scientific and regulatory affairs for CRN. “That would be the worst outcome. Some people want it to be withdrawn, others want substantial revisions. But doing nothing would be detrimental; it would be unfair to leave the industry in limbo.”²³

References

   2. Ullman M and Dougherty L. “Re: Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues. Docket No. FDA-2011-D-0376.” Letter to FDA. August 8, 2011

   3.  Harkin T and Hatch OG. Letter to Margaret Hamburg. December 22, 2011.

     4. McGuffin M and Young AL. “Comments of the American Herbal Products Association on Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues.” Letter to FDA. December 2, 2011.

     5. Dietary Supplement Health And Education Act of 1994. PL 103-417. 103^rd Cong, 2^nd Sess (1994). Available at http://www.health.gov/dietsupp/ch1.htm.

6. Industry Responds to Top NDI Draft Guidance Issues: Addressing the Biggest Questions that Affect Your Business. Natural Products Insider. September 1, 2011. Available at http://www.naturalproductsinsider.com/galleries/2011/08/slide-show-unpa-ndi-conference.aspx. Accessed December 3, 2011.

    7. Granato H. NDI Draft Guidance: Perceptions, Needs, & Strategy. Assessing the Supplement Industry’s Understanding of NDI Notifications. Natural Products Insider. November 14, 2011. Available at http://npi.virgocreative.com/reports/2011/11/ndi-draft-guidance.aspx. Accessed December 14, 2011.

8. Fabricant D. FDA Perspective. UNPA Webinar: The NDI Guidance and Comments: What Now? December 21, 2011.

9. Daniells S. UNPA: NDI Draft Guidance is ‘Needlessly Burdensome’ & Does Not Advance Overall Safety of Dietary Supplements. Nutraingredients-usa.com. December 6, 2011. Available at http://www.nutraingredients-usa.com/Regulation/UNPA-NDI-draft-guidance-is-needlessly-burdensome-does-not-advance-overall-safety-of-dietary-supplements. Accessed December 10, 2011.

10. Supplements Community Wrap Up. New Dietary Ingredient (NDI) Guidance. SupplySide Community. July 2011.  Available at http://community.supplysideshow.com/reports_inner.php?ReportIcode=14. Accessed December 5, 2011.

11. Mister S. NDIs and the Burden of Proof. Natural Products Insider. July 18, 2011. Available at http://www.naturalproductsinsider.com/articles/2011/07/ndis-and-the-burden-of-proof.aspx. Accessed December 5, 2011.

12. Majeed S and LeGall B. Re: Docket No. FDA-2011-D-0376. Sabinsa Corporation. November 28, 2011.

13. CRN, NHPA Call for NDI Draft Guidance Withdrawal. Natural Products Insider. December 2, 2011. Available at http://www.naturalproductsinsider.com/news/2011/12/crn-chpa-call-for-ndi-draft-guidance-withdrawal.aspx. Accessed December 2, 2011.

14. Noonan C and Noonan P. New Dietary Ingredients: DSHEA Provides Protection from Potentially Unsafe New Ingredients with no Prior Market History in the U.S. HerbalGram. 2004; 63:70-74.

     16. Mister S. DSHEA’s Architect Hosts NDI Town Hall. SupplySide Community. October 24, 2011. Available at http://community.supplysideshow.com/blog_page.php?BlogIcode=252. Accessed December 2, 2011.

17. Watson E. ANH-USA: ‘Unworkable and Irrational’ NDI Guidance is Rulemaking by the Backdoor. Nutraingredients-usa.com. December 6, 2011. Available at http://www.nutraingredients-usa.com/Regulation/ANH-USA-Unworkable-and-irrational-NDI-guidance-is-rulemaking-by-the-backdoor. Accessed December 20, 2011.

18. Why Solvent Change Triggers NDI. Natural Products Insider. August 3, 2011. Available at http://www.naturalproductsinsider.com/news/2011/08/why-fda-wants-ndi-notifications-for-natural-solve.aspx. Accessed December 16, 2011.

19. Congress’ NDI Intent. Natural Products Insider. July 29, 2011. Available at http://www.naturalproductsinsider.com/news/2011/07/congress-ndi-intent.aspx. Accessed December 16, 2011.

20. Blumenthal M. Re: Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues. American Botanical Council. December 2, 2011. Available at http://abc.herbalgram.org/site/PageServer?pagename=ABC_NDI_Comments_Submitted_to_FDA. Accessed December 2, 2011.

21. Tipps S. Legal Tips: Save Your Business. Whole Foods Magazine. December 2011;(34)2:42-44.

22. Venardos J. “Re: Docket No. 76 Fed. Reg. 39111-39112 (July 5, 2011) Docket No. FDA-2011-D-0376.” Herbalife letter to FDA. October 13, 2011.

23. Daniells S. Trade Associations United in Calls for ‘Substantial Overhaul’ of NDI Draft Guidance. Nutraingredients USA. December 7, 2011. Available at http://www.nutraingredients-usa.com/Regulation/Trade-associations-united-in-calls-for-substantial-overhaul-of-NDI-draft-guidance. Accessed December 21, 2011.